Secretin preparation having prolonged action and the procedure of manufacture

ABSTRACT

SECRETIN PREPARATIION HAVING PROLOGNED ACTION WHICH COMPRISES A CONTENT OF (A) SECRETIN (B) AN AQUEOUS SOLUTION OF GELATIN-DRIVATIVE CROSS-LINKED WITH HEXAMETHYLENE-DIISOCYANATE AND (C) POLYPHLORETIN PHOSPHATE AND A PROCESS FOR THE MANUFACTURE THEREOF.

United States Patent Oifice 3,749 774 SECRETIN PREPARATION HAVING PROLONGED ACTION AND THE PROCEDURE OF MANU- FACTURE 3,749,774 Patented July 31, 1973 erably at 6.5 to 7.2. The solution is sterilized 'by filtration,

pipetted into sterile bottles and optionally lyophilised.

The ratio of the individual components may be varied within determined limits. Generally, polyphloretin phos- Rudol l 5 phate and gelatin derivative are used in excess. Advanf s ig gfs figg ggggag ggg gg ggg gsgg tageously, from 15 to 30 mg. of polyphloretm phosphate Hoechst Aktiengesellschaft vormals Meister Lucius & and q 20 to 80 m of gelfltm denvfitlve are P pruning, Frankf t amMain Germany approximately 75 chmcal units (defimtion according to No Drawing. Filed Jan. 27, 1972, Ser. No. 221,414 Iorpes and Mutt, Acta p y Scam, 66 (19 Claims priority, application Germany, Jan. 30, 1971, pp. 316-325) of secretin. To determine the prolonged P 21 04 344.7 action of secretin the pancreatic juice flow was measured Int. Cl-

. on the dog. US. Cl. 424-177 2 Chums Fasted dogs, weighing from 12 to 20 kg. were intravenously anesthetized with pentobarbital. The pancreatic ABSTRACT OF THE DISCLOSURE 15 ductus was opened between the pancreas and duodenum, a polyethylene tube was introduced into the lumen of seclzetm Preparatlon having Prolonged actlon whlch the excretory duct so that the pancreatic juice could be comprlses a content of obtained in pure state and the volume of secretion could (a) secretin be registered continuously. In order to avoid endogenous (b) an aqueous solution of gelatin-derivative cross-linked {t releases t gasmc and the blle Secre' ion, the pylorus was llgated, the ductus choledochus was g a a i g i i g and f th tied off and the bile led oif. Optionally, accessory pan- P Osp a e an aprocess or e m creatic ducts were tied off. The animals were given a ac are ereo continuous intravenous infusion of about 10 ml./h. of physiological sodium chloride. Secretin was administered The present invention relates to a secretin preparation intravenously in the femoral vein via catheters of synhaving a prolonged action and the method for manufacthetic material, subcutaneously at the side of the thorax turing said preparation. and intramuscularly in the glutual muscles. The secretin This secretin derivative having prolonged action is obused was pure natural secretin (Gastrointestinal Hormontained by combining Research Unit, Chem. Abt. Karolinska Institutet, Stockholm, Batch No. 17041). For the depot tests the secretin an aqueous Solution of secretin, dosage was always 75 units per dog dissolved in 1 ml. of

( the aqueous Solution of a gelatin derivative physiological sodium chloride or in the corresponding linked With hexamethyiene-diisocyanate, P p depot carrier. The following depot preparations have been cording to German Pats. Nos. 1,118,?2 or 1,155,133 d;

(hereinafter referred to as gelatin erivative an 30m g./ml. of polyphloretin phosphate (PPP) (c) the aqueous solution of polyphloretm phosphate 15 rug/ml. of PPP+20 mg./ml. of gelatine derivative 30 mg./ml. of PPP+4O mg./ml. of gelatine derivative and optionally lyophihsing the solution thus obtained 40 30 g L o PPP+80 gj of g t e d r a e The secretin can be obtained from natural sources or All Solutions were adjusted at PH 6.8 and prepared on can be prepared synthetically. Thegelatm derivative used the test day immediatgly before the application Three in accordance with the invention is a partially degraded injections per dog were given, always in the same order; gelatin cross-linked with hexamethylene-dnsocyanate. It is prepared according to German Pat 1,118,792 or (1) Secret n d ssolved n a 0.9% sodium chloride solution 1,155,134 or to the corresponding US. Pat. No. 3,057,782. secretin dissolved the depot m The manufacture f polyphloretin phosphate is (3) Secretin dissolved in a 0.9% sodium chloride soluscribed in German Pat. No. 929,664.

To manufacture the depot preparations the individual Th volume f h t d pancreatic j i was meascomponents for example, separately dissvlved n ured in 15 minute intervals. Since dogs are carnivorous the acid Solution of Polyphioretin Phosphate being animals, and have almost no basal pancreatic secretion, neutralized With an inorganic base, Such as Potassium the end of the secretin action could be exactly evaluated hydroxide, sodium hydroxide or ammonia, or with an by means of a pancreatic juice flow diagram and the organic base, for example, a tertiary amine, such as triperiod of activity could be calculated. ethyl amine or N-ethyl-piperidine. First the solutions of As shown in Table I, the depot preparations in acsecretin and gelatin derivative are combined and then cordance ith th i ti id a considerable the Solution of polyphloretin Phosphate is added- The longation of the secretin effect. This secretin preparation, solution is adjusted to isotonicity with sodium chloride or in acco d nce with the present invention, is a valuable a physiologically acceptable organic compound, for exmedicament. It may be used for diminishing the gastric ample an amino acid, such as sodium glutamate and the secretion in the case of ulcer diseases and for the stimupH is then adjusted to the range between 5.5 to 7.5, preflation of pancreatic juice secretion.

TABLE I Pancreatic juice flow after subcutaneous secretin injection Depot eflect Period of activity Percent prolongation of the 1. Injection 2.Injection 3.Iniection period of Depotprepm'ation Normal-secretin Depot-secretin" Normal-secretin activity 15 mg./ml. of PPP plus 20 mgJml. of gelatine-derivative 3 hr. 45 2.21: 5 n lir: g fiflaa 13g 33 iiiifii: 3i 1 1 Biii i3 13273 13 Ziiiiiifiififiiifiiiifi: iii: it min in. 45 min 2 hr. 30 min 271 Norn-PPI =Po1yph1oretinphcsphate.

3 ,We claim:

1. Secretin injectable dosage unit preparation having prolonged action which comprises a content of (a) secretin, in clinically effective dosage amount, in a depot carrier of (b) an aqueous solution of gelatin derivative crosslinked, With hexamethylene-diisocyanate and (c) polyphloretin phosphate. 2. Secretin preparation having prolonged action as claimed in claim 1, which has a. content of (a) 75 clinical units of secretin (b) 20-80 mg. of gelatin derivative cross-linked with hexamethylene diisocyanate (0) 15-30 mg. of polyphloretin phosphate.

References Cited UNITED STATES PATENTS 2,962,515 11/1960 Diczfalusy et a1. 26092O 3,057,782 10/1962 Lindner et al. 424177 4 6/1965 Hogberg et al 424-177 X 5/ 1967 Schwick et al 424360 X 6/1967 Jorpes et al. 424-177 7/1967 Barron et a1. 424-177 X 4/1971 Johnson et a1 424-360 X 2/1972 Geller 424177 X FOREIGN PATENTS 7/ 1957 Great Britain.

OTHER REFERENCES Graumann ct al.: Acta 'Histochem. 6: 254262 (1959). Hedner: Acta Endocrinol 43(4): 599-509 (1963). Colldahl: Acta Endocrino147(4): 565-573 (1964).

15 SHEP K. ROSE, Primary Examiner US. Cl. X.R. 

